US10307470B2ActiveUtilityA1

Antibody-mediated anti-tumor activity induced by Reishi mushroom polysaccharides

59
Assignee: ACADEMIA SINICAPriority: Jul 26, 2013Filed: Jul 26, 2014Granted: Jun 4, 2019
Est. expiryJul 26, 2033(~7 yrs left)· nominal 20-yr term from priority
Inventors:Chi-Huey WongChung-Yi WuHsien-Yeh HsuShih-Fen LiaoChi-Hui Liang
A61K 2039/575A61K 2039/55572A61P 35/00A61K 36/074A61K 39/0002A61K 39/0011A61K 39/00118A61K 39/001173
59
PatentIndex Score
0
Cited by
5
References
39
Claims

Abstract

Immunogenic compositions, cancer vaccines and methods for treating cancer comprising FMS, the fucose-enriched polysaccharide fraction from Reishi F3, are provided. Compositions comprise fucose-enriched Reishi polysaccharide fraction (FMS) MW=˜35 kDa, wherein the FMS is isolated by size-exclusion chromatography from Reishi F3, and the FMS comprises polysaccharides having primarily a backbone selected from 1,4-mannan and 1,6-α-galactan, wherein the backbone is linked to a terminal fucose-containing side-chain Immunogenic compositions comprising glycolipid adjuvants are provided. Antibodies generated by immunogenic compositions disclosed herein bind cancer cells comprising antigens Globo H, Globo H, Gb3, Gb4, Gb5 (SSEA-3) and SSEA-4 on the cell surface.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
       1. An immunogenic composition, consisting of:
 a fucose-enriched Reishi polysaccharide fraction (FMS) of average molecular weight 35 kDa, wherein the FMS is isolated by size-exclusion chromatography from Reishi F3, and wherein the FMS comprises polysaccharides having primarily a backbone selected from 1,4-mannan and 1,6-α-galactan, wherein the backbone is linked to a terminal fucose-containing side-chain; and 
 an adjuvant, wherein the adjuvant is a glycolipid. 
 
     
     
       2. The immunogenic composition of  claim 1 , wherein the backbone is linked to a terminal fucose-containing side-chain through one or more linkages selected from the group consisting of Fucα1-2Gal, Fucα1-3/4Man, Fucα1-4Xyl and Fucα1-2Fuc. 
     
     
       3. The immunogenic composition of  claim 1 , wherein the FMS comprises primarily of fucose, xylose, galactose and mannose. 
     
     
       4. The immunogenic composition of  claim 1 , wherein the FMS comprises glucose, glucosamine and galactosamine. 
     
     
       5. The immunogenic composition of  claim 1 , wherein the adjuvant is a synthetic analog of α-GalCer selected from the group consisting of: (7DW8-5) and (C34) 
       
         
           
           
               
               
           
         
       
     
     
       6. The immunogenic composition of  claim 1 , wherein administration of the composition to a mammal induces IgG antibodies. 
     
     
       7. The immunogenic composition of  claim 1 , wherein administration of the composition to a mammal induces IgM antibodies. 
     
     
       8. The immunogenic composition of  claim 1 , wherein the composition induces antibodies that specifically bind to at least one of the tumor-associated antigens selected from the group consisting of Globo H, Gb3 (Galα1-4Galß1-4Glc), Gb4 (GalNAcß1-3Galα1-4Galß1-4Glc), stage-specific embryonic antigen-3 (SSEA-3; Gb-5; or Galß1-3GalNAcß1-3Galα1-4Galß1-4Glc) and SSEA-4 (Neu5Acα2-3Galß1-3GalNAcß1-3Galα1-4Galß1-4Glc). 
     
     
       9. The immunogenic composition of  claim 1 , wherein the composition induces antibodies that specifically bind to a glycan antigen comprising a common structure: Fucα1-2Galβ1-3GalNAc-R in the non-reducing termini. 
     
     
       10. The immunogenic composition of  claim 9 , wherein the composition induces antibodies that specifically bind to an antigen comprising an additional disaccharide extension in the reducing end of Fucα1-2Galβ1-3GalNAc-R, wherein the disaccharide moiety is selected from the group consisting of: Fucα1-2Gal-R; Fucα1-3/4Man-R; Fucα1-4Xyl-R and Fucα1-2Fuc-R. 
     
     
       11. The immunogenic composition of  claim 10 , wherein the composition induces antibodies that specifically bind to α-L-fucose-specific lectin or UEA-I ( Ulex europaeus  agglutinin-I). 
     
     
       12. The immunogenic composition of  claim 1 , wherein the composition induces antibodies that specifically bind to a glycan antigen comprising a blood group ABH determinant. 
     
     
       13. The immunogenic composition of  claim 1 , wherein the composition induces antibodies that trigger complement-dependent cytotoxicity (CDC) in a cancer cell. 
     
     
       14. The immunogenic composition of  claim 13 , wherein the CDC activity is sufficient to reduce tumor size in a lung cancer. 
     
     
       15. The immunogenic composition of  claim 13 , wherein administration of the composition results in decrease of serum levels of monocyte chemoattractant protein-1 (MCP-1). 
     
     
       16. A cancer vaccine comprising the immunogenic composition of  claim 1 ; and
 a pharmaceutically acceptable excipient, 
 wherein pretreatment with the composition causes greater reduction of tumor volume in non-small-cell lung cancer (NSCLC) as compared to treatment after induction of the cancer. 
 
     
     
       17. The cancer vaccine of  claim 16 , wherein levels of monocyte chemoattractant protein-1 (MCP-1), chemokine (C-X-C motif) ligand 1 (CXCL1/KC) and granulocyte colony-stimulating factor (G-CSF) are decreased in mammals pretreated with the composition. 
     
     
       18. The cancer vaccine of  claim 16 , wherein the adjuvant is a synthetic analog of α-GalCer selected from the group consisting of: (7DW8-5) and (C34) 
       
         
           
           
               
               
           
         
       
     
     
       19. The cancer vaccine of  claim 16 , wherein administration of the composition to a mammal induces IgG antibodies. 
     
     
       20. The cancer vaccine of  claim 16 , wherein administration of the composition to a mammal induces IgM antibodies. 
     
     
       21. A therapeutic against cancer cells, the therapeutic consisting of:
 a fucose-enriched Reishi polysaccharide fraction (FMS) of average molecular weight 35 kDa, wherein the FMS is isolated by size-exclusion chromatography from Reishi F3, and wherein the FMS comprises polysaccharides having primarily a backbone selected from 1,4-mannan and 1,6-α-galactan, wherein the backbone is linked to a terminal fucose-containing side-chain; and 
 an adjuvant, wherein the adjuvant is a glycolipid. 
 
     
     
       22. The therapeutic of  claim 21 , wherein administration of the therapeutic to a subject induces production of antibodies that recognize Globo H or a GloboH-related glycan antigen expressed on a cancer cell. 
     
     
       23. The therapeutic of  claim 22 , wherein the Globo H or a GloboH-related glycan antigen is selected from the group consisting of Globo H, Gb3 (Galα1-4Galß1-4Glc), Gb4 (GalNAcß1-3Galα1-4Galß1-4Glc), stage-specific embryonic antigen-3 (SSEA-3; Gb-5; or Galß1-3GalNAcß1-3Galα1-4Galß1-4Glc) and SSEA-4 (Neu5Acα2-3Galß1-3GalNAcß1-3Galα1-4Galß1-4Glc). 
     
     
       24. The therapeutic of  claim 21 , wherein the cancer cells are non-small-cell lung cancer (NSCLC) cells. 
     
     
       25. The therapeutic of  claim 21 , wherein the backbone is linked to a terminal fucose-containing side-chain through one or more linkages selected from the group consisting of Fucα1-2Gal, Fucα1-3/4Man, Fucα1-4Xyl and Fucα1-2Fuc. 
     
     
       26. The therapeutic of  claim 21 , wherein the FMS comprises primarily of fucose, xylose, galactose and mannose. 
     
     
       27. The therapeutic of  claim 21 , wherein the FMS comprises glucose, glucosamine and galactosamine. 
     
     
       28. A method of reducing severity and/or frequency of symptoms of a tumor, wherein the adjuvant is a glycolipid, the method comprising:
 1 administering to a subject in need thereof an immunogenic composition consisting of: a fucose-enriched Reishi polysaccharide fraction (FMS) of average molecular weight 35 kDa, wherein the FMS is isolated by size-exclusion chromatography from Reishi F3, and wherein the FMS comprises polysaccharides having primarily a backbone selected from 1,4-mannan and 1,6-α-galactan, wherein the backbone is linked to a terminal fucose-containing side-chain; and an adjuvant, in an amount effective to 
 induce an immune response that causes inhibition of tumor growth, wherein the adjuvant is glycolipid. 
 
     
     
       29. The method of  claim 28 , wherein the backbone is linked to a terminal fucose-containing side-chain through one or more linkages selected from the group consisting of Fucα1-2Gal, Fucα1-3/4Man, Fucα1-4Xyl and Fucα1-2Fuc. 
     
     
       30. The method of  claim 28 , wherein the FMS comprises primarily of fucose, xylose, galactose and mannose. 
     
     
       31. The method of  claim 30 , wherein the adjuvant is a synthetic analog of α-GalCer selected from the group consisting of: 7DW8-5 and C34 
       
         
           
           
               
               
           
         
       
     
     
       32. The method of  claim 28 , wherein the composition is administered in an amount effective to induce IgG antibodies. 
     
     
       33. The method of  claim 28 , wherein the composition is administered in an amount effective to induce IgM antibodies. 
     
     
       34. The method of  claim 28 , wherein the composition is administered in an amount effective to induce antibodies that specifically binds to at least one of the tumor-associated antigens selected from the group consisting of Globo H, Gb3 (Galα1-4Galß1-4Glc), Gb4 (GalNAcß1-3Galα1-4Galß1-4Glc), stage-specific embryonic antigen-3 (SSEA-3; Gb-5; or Galß1-3GalNAcß1-3Galα1-4Galß1-4Glc) and SSEA-4 (Neu5Acα2-3Galß1-3GalNAcß1-3Galα1-4Galß1-4Glc). 
     
     
       35. The method of  claim 28 , wherein the composition is administered in an amount effective to induce antibodies that specifically bind to a glycan antigen comprising a common structure: Fucα1-2Galβ1-3GalNAc-R in the non-reducing termini. 
     
     
       36. The method of  claim 35 , wherein the composition is administered in an amount effective to induce antibodies that specifically bind to an antigen comprising an additional disaccharide extension in the reducing end of Fucα1-2Galβ1-3GalNAc-R, wherein the disaccharide moiety is selected from the group consisting of: Fucα1-2Gal-R; Fucα1-3/4Man-R; Fucα1-4Xyl-R and Fucα1-2Fuc-R. 
     
     
       37. The immunogenic composition of  claim 1 , wherein the FMS comprises primarily of fucose, xylose, galactose and mannose in the ratio of 2:1.5:2.5:3.5 as determined by a high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) method. 
     
     
       38. The therapeutic of  claim 21 , wherein the FMS comprises primarily of fucose, xylose, galactose and mannose in the ratio of 2:1.5:2.5:3.5 as determined by a high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) method. 
     
     
       39. The method of  claim 28 , wherein the FMS comprises primarily of fucose, xylose, galactose and mannose in the ratio of 2:1.5:2.5:3.5 as determined by a high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) method.

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